Liu Min-Chen, Ma Xiao-Qiong, Xu Yong, Peng Li-Hua, Han Min, Gao Jian-Qing
College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
National Clinical Research Base of Traditional Chinese Medicine, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou 310006, China.
J Pharm Biomed Anal. 2016 Feb 5;119:76-83. doi: 10.1016/j.jpba.2015.11.017. Epub 2015 Nov 18.
A previous study has reported diacid metabolite (DM) as the stable form of norcantharidin (NCTD), which is almost 100% metabolized to DM-NCTD. However, the unreliable pharmacokinetic characteristics of DM-NCTD could result in low bioavailability, hindering the clinical use of DM-NCTD in the treatment of diseases. A liposomal drug delivery system could overcome the shortcomings of DM-NCTD by improving the relative bioavailability (Fr), reducing drug toxicity, and increasing the therapeutic efficacy. However, there are no data concerning the pharmacokinetics of a DM-NCTD-loaded liposomal drug delivery system in animals, which is required for assessing its safety profile. Therefore, a rapid and sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and validated for the determination of DM-NCTD in mouse plasma. Standard curves were linear (r=0.9966) over the range 10.0-1.00×10(4)ng/ml in mouse plasma with a lower limit of quantification (LLOQ) of 10ng/ml. This study successfully investigated the pharmacokinetics of DM-NCTD and DM-NCTD encapsulated in polyethylene glycol (PEG)-Liposomes (DM-NCTD/PEG-Liposome) or folic acid (FA)-PEG-Liposomes (DM-NCTD/FA-PEG-Liposome) in Kunming mice after a single intravenous dose of 2mg/kg. The plasma profile data of the three groups adhered to a two-compartment model. Compared with the DM-NCTD group, the Liposome groups had longer circulation times following intravenous administration in mice, and the Fr of DM-NCTD increased significantly (P<0.05). Furthermore, the area under the concentration-time curve (AUC) declined with an increase in the volume of distribution (Vd) from the PEG-Liposome to the FA-PEG-Liposome groups, which indicates a more efficient removal of the drug from the plasma of the FA-PEG-Liposome group. This result suggests a possible increased risk of DM-NCTD intoxication in normal tissues with FA-PEG-Liposomes. Based on this study, further investigation of the biodistribution of DM-NCTD/FA-PEG-Liposomes in healthy animals is warranted. In addition, the plausibility of formulating a safe DM-NCTD-loaded system without increasing toxicity against normal tissues needs to be determined.
先前的一项研究报道二酸代谢物（DM）是去甲斑蝥素（NCTD）的稳定形式，NCTD几乎100%代谢为DM-NCTD。然而，DM-NCTD不可靠的药代动力学特征可能导致生物利用度低，阻碍了DM-NCTD在疾病治疗中的临床应用。脂质体药物递送系统可以通过提高相对生物利用度（Fr）、降低药物毒性和提高治疗效果来克服DM-NCTD的缺点。然而，目前尚无关于载有DM-NCTD的脂质体药物递送系统在动物体内药代动力学的数据，而这对于评估其安全性至关重要。因此，开发并验证了一种快速灵敏的液相色谱-串联质谱（LC-MS/MS）方法用于测定小鼠血浆中的DM-NCTD。在小鼠血浆中，标准曲线在10.0-1.00×10(4)ng/ml范围内呈线性（r = 0.9966），定量下限（LLOQ）为10ng/ml。本研究成功考察了单次静脉注射2mg/kg后，昆明小鼠体内DM-NCTD以及包裹于聚乙二醇（PEG）-脂质体（DM-NCTD/PEG-脂质体）或叶酸（FA）-PEG-脂质体（DM-NCTD/FA-PEG-脂质体）中的DM-NCTD的药代动力学。三组的血浆特征数据均符合二室模型。与DM-NCTD组相比，脂质体组在小鼠静脉给药后的循环时间更长，DM-NCTD的Fr显著增加（P<0.05）。此外，从PEG-脂质体组到FA-PEG-脂质体组，浓度-时间曲线下面积（AUC）下降，分布容积（Vd）增加，这表明FA-PEG-脂质体组从血浆中清除药物的效率更高。这一结果表明，使用FA-PEG-脂质体时，正常组织中DM-NCTD中毒的风险可能增加。基于本研究，有必要进一步研究DM-NCTD/FA-PEG-脂质体在健康动物体内的生物分布。此外，需要确定在不增加对正常组织毒性的情况下制备安全的载有DM-NCTD系统的可行性。
